A Bispecific DLL3/CD3 IgG-Like T-Cell Engaging Antibody Induces Antitumor Responses in Small Cell Lung Cancer

Clin Cancer Res. 2020 Oct 1;26(19):5258-5268. doi: 10.1158/1078-0432.CCR-20-0926. Epub 2020 Jun 18.


Purpose: Small cell lung cancer (SCLC) is the most lethal and aggressive subtype of lung carcinoma characterized by highly chemotherapy-resistant recurrence in the majority of patients. To effectively treat SCLC, we have developed a unique and novel IgG-like T-cell engaging bispecific antibody (ITE) that potently redirects T-cells to specifically lyse SCLC cells expressing Delta-like ligand 3 (DLL3), an antigen that is frequently expressed on the cell surface of SCLC cells, with no to very little detectable expression in normal tissues.

Experimental design: The antitumor activity and mode of action of DLL3/CD3 ITE was evaluated in vitro using SCLC cell lines and primary human effector cells and in vivo in an SCLC xenograft model reconstituted with human CD3+ T-cells.

Results: Selective binding of DLL3/CD3 ITE to DLL3-positive tumor cells and T-cells induces formation of an immunological synapse resulting in tumor cell lysis and activation of T-cells. In a human T-cell engrafted xenograft model, the DLL3/CD3 ITE leads to an increase in infiltration of T-cells into the tumor tissue resulting in apoptosis of the tumor cells and tumor regression. Consistent with the mode of action, the DLL3/CD3 ITE treatment led to upregulation of PD-1, PD-L1, and LAG-3.

Conclusions: This study highlights the ability of the DLL3/CD3 ITE to induce strictly DLL3-dependent T-cell redirected lysis of tumor cells and recruitment of T-cells into noninflamed tumor tissues leading to tumor regression in a preclinical in vivo model. These data support clinical testing of the DLL3/CD3 ITE in patients with SCLC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Bispecific / pharmacology
  • Antigens, CD / genetics
  • Apoptosis / drug effects
  • B7-H1 Antigen / genetics
  • CD3 Complex / genetics*
  • Cell Lineage / drug effects
  • Cell Lineage / immunology
  • Cell Proliferation / drug effects*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects
  • Heterografts
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Lymphocyte Activation Gene 3 Protein
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Male
  • Membrane Proteins / genetics*
  • Mice
  • Programmed Cell Death 1 Receptor / genetics
  • Small Cell Lung Carcinoma / drug therapy*
  • Small Cell Lung Carcinoma / genetics
  • Small Cell Lung Carcinoma / immunology
  • Small Cell Lung Carcinoma / pathology
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology


  • Antibodies, Bispecific
  • Antigens, CD
  • B7-H1 Antigen
  • CD3 Complex
  • DLL3 protein, human
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Programmed Cell Death 1 Receptor
  • Lymphocyte Activation Gene 3 Protein